The present invention relates to a family of novel non-psychotropic cannabinoids, and to pharmaceutical compositions containing them, which are useful for preventing or alleviating neurotoxicity and inflammation. Said pharmaceutical compositions comprise as their active ingredient the stereospecific (+) enantiomers, having (3S,4S) configuration, of xcex946-tetrahydrocannabinol (THC) type compounds of general formula (I), as defined hereinbelow. 
The identification of tetrahydrocannabinol (THC) as the active principle of marijuana (Cannabis sativa) prompted medicinal chemists to develop numerous cannabinoid analogs (reviewed by Barth, in Exp. Opin. Ther. Patents 8:301-313, 1998). These novel compounds were designed to exhibit the beneficial properties of THC without the accompanying psychotropic effects, which limit its therapeutic utility. Potential therapeutic applications have classically included known attributes of marijuana itself such as anti-emesis, analgesia, antiglaucoma and appetite stimulation. More recently recognized roles for non-psychotropic cannabinoids are as neuroprotective and anti-inflammatory agents.
Chronic degenerative changes, as well as delayed or secondary neuronal damage following direct injury to the central nervous system (CNS), may result from pathologic changes in the brain""s endogenous neurochemical systems. Although the precise mechanisms mediating secondary damage are poorly understood, post-traumatic neurochemical changes may include overactivation of neurotransmitter release or re-uptake, changes in presynaptic or postsynaptic receptor binding, or the pathologic release or synthesis of endogenous factors. The identification and characterization of these factors and of the timing of the neurochemical cascade after CNS injury provides a window of opportunity for treatment with pharmacologic agents that modify synthesis, release, receptor binding, or physiologic activity with subsequent attenuation of neuronal damage and improvement in outcome. A number of studies have suggested that modification of post-injury events through pharmacologic intervention can promote functional recovery in both a variety of animal models and clinical CNS injury. Pharmacologic manipulation of endogenous systems by such diverse pharmacologic agents as anticholinergics, excitatory amino acid antagonists, including specifically NMDA receptor antagonists, endogenous opioid antagonists, catecholamines, serotonin antagonists, modulators of arachidonic acid, antioxidants and free radical scavengers, steroid and lipid peroxidation inhibitors, platelet activating factor antagonists, anion exchange inhibitors, magnesium, gangliosides, and calcium channel antagonists have all been suggested to potentially improve functional outcome after brain injury (McIntosh, J. Neurotrauma 10:215-243, 1993).
The pathogenesis of a diverse group of neurological disorders has been linked to excessive activation of excitatory amino acid receptors. These disorders include epilepsy, focal and global ischemia, CNS trauma, and various forms of neurodegeneration including Huntington""s chorea, Parkinson""s disease and Alzheimer""s disease. There has been extensive effort invested in the development of excitatory amino acid receptor antagonists as therapeutic agents (Rogawski, Trends in Pharmacol. Sci. 14:325-331, 1993 and Danbolt, Progress in Neurobiology 65:1-105, 2001).
Since no proven effective therapy for neuronal injury, or degeneration, is yet known, and, for example, stroke alone is one of the leading causes of death in many countries, the importance of finding such therapeutic NMDA antagonists is self-evident. It will be important to determine whether certain NMDA receptor antagonists are more effectivexe2x80x94or have fewer side effectsxe2x80x94than others in specific disease states.
Some of the compounds of general Formula (I) are disclosed in U.S. Pat. No. 4,179,517 and 4,876,276. As disclosed in said U.S. patents, these essentially pure synthetic (+)-(3S,4S)-THC derivatives and analogues are devoid of any undesired cannabimimetic psychotropic side effects. These known compounds have been described as having analgesic, antiemetic and antiglaucoma activity.
A particular compound of interest of Formula I, namely 1,1 dimethyl heptyl-(3S,4S)-7-hydroxy-xcex946-tetrahydrocannabinol, is disclosed in U.S. Pat. No. 4,876,276, and denoted therein as HU-211, and subsequently assigned the trivial chemical name dexanabinol. HU-211 was unexpectedly discovered to possess neuroprotective attributes, which may be ascribed to its activity as a non-competitive antagonist at the NMDA receptor, as disclosed in U.S. Pat. Nos. 5,284,867 and 5,521,215. Certain ester derivatives of dexanabinol are also active in neuroprotection, as disclosed in U.S. Pat. No. 6,096,740 as are the carboxylic acid derivatives of HU-211 as disclosed in U.S. Pat. Nos. 5,538,993 and 5,635,530.
Besides NMDA receptor blocking activity, dexanabinol and its ester derivatives were further shown to possess anti-oxidative and anti-inflammatory properties, which may contribute to their efficacy in preventing or alleviating ischemic damage to tissues.
In addition, derivatives of HU-211 were surprisingly shown to possess immunomodulatory potential due to their ability to inhibit Tumor Necrosis Factor alpha as disclosed in U.S. Pat. No. 5,932,610.
Certain natural non-psychotropic cannabinoids, including the derivative cannabidiol, have been found to have antioxidant properties unrelated to NMDA receptor antagonism as disclosed in WO 99/53917.
Endogenous ligands of the cannabinoid receptors (Mechoulam, et al., Endocannabinoids, Eur J. Pharmacol. 359:1-18, 1998) have been identified as being arachidonyl derivatives including 2-arachidonyl glycerol, and arachidonyl-ethanolamide (anandamide). Thus, these endocannabinoids are chemically related to certain metabolites in the arachidonic acid pathway.
A family of compounds known to exhibit inflammatory properties is the prostaglandins (PG). Prostaglandins are arachidonic acid metabolites, produced by the action of cyclooxygenase (COX) also known as PGH synthase. The first step in the production of prostaglandins from arachidonic acid (AA) is the bis-oxygenation of arachidonic acid to prostaglandin PGG2. This is followed by reduction to PGH2 in a peroxidase reaction. COX catalyzes both of these reactions. Two isoforms of COX have been identified, COX-1 and COX-2. Although both perform the same catalytic activity they differ in tissue distribution, regulation and expression (Williams and DuBois Am J. Physiol. 270:G393-400, 1996).
COX-1 is constitutively expressed and appears to be involved in the physiological production of PGs. Although COX-2 has a normal pattern of expression in some body tissues it is primarily an inducible form that is expressed upon prolonged exposure to chemical mediators including cytokines and endotoxin (reviewed in Golden and Abramson, Selective Cyclooxygenase-2 inhibitors, Osteoartritis 25:359-378, 1999) Pain and inflammation in certain pathological processes are mediated by the COX-2 dependent production of PGE2. There is considerable interest in developing anti-inflammatory therapeutic strategies that block the activity of COX-2 and the biosynthesis of PGE2 resulting from activation of the Arachidonic acid/prostaglandin (AA/PG) biosynthetic pathway.
Attenuation of COX-2 activity is correlated with a reduction in pain, inflammation and fever. For example, the NSAIDs (non-steroidal anti-inflammatory drugs) act by blocking the COX enzymes. A reduction of 40-50% in the colon cancer rate among cardiovascular patients in the US who are given prophylactic doses of aspirin (a common NSAID) was also shown to be related to a decrease in COX-2 expression (Smalley and DuBois, Adv Pharmacol 39:1-20, 1997).
Therapeutic strategies that target this pathway are sought to prevent and treat a variety of diseases and symptoms such as neuronal degeneration in diseases as Alzheimer""s disease or Parkinson""s disease, neuronal trauma associated with seizures, brain or CNS damage, inflammation associated with rheumatoid arthritis; bone resorption and colonic polyposis and colorectal cancer (reviewed in Lipsky, J Rheumatol 26: Suppl 56:25-30, 1999). U.S. Pat. No. 5,840,746 teaches the method of treating neurodegenerative disease by administering non-steroidal COX-2 inhibitors that specifically bind to COX-2. Inflammation has also been implicated as part of the pathogenesis in myocardial infarction, atheroma, unstable angina and other cardiac disorders (Ross, New England J Med 340:115-126, 1999).
There is an unmet need for and it would be advantageous to have novel non-psychotropic cannabinoid compounds that exert their effects via a plurality of mechanisms. Ideally, in addition to having said analgesic, antiemetic and anti-glaucoma activities, they would also be effective against the diseases and conditions mentioned above. The mechanisms invoked in these pleitropic effects include their action as excitatory amino acid receptor blockers, for example NMDA-receptor or glutamate-blockers or interaction with the glycine receptor, or as inhibitors of either the oxidative, cytokine, nitric oxide or AA/PG pathways, including the cyclooxygenase and lipoxygenase and are effective in the alleviation and treatment of many of the abnormal states involving said neurotransmitter or pathway mediated toxicity. The present invention now provides such compounds.
The present invention relates to pharmacologically acceptable non-psychotropic cannabinoids. These compounds act as agents that can afford neuroprotection by exhibiting anti-inflammatory activity, and/or antioxidative activity, and/or the capacity to block the AA/PG or lipoxygenase pathway, or the nitric oxide or cytokine pathways and/or to block excitatory amino acid mediated toxicity by interaction at specific receptors, such as glutamate receptors. In addition, the present provides agents that can afford neuroprotection by combined anti-inflammatory, antioxidative and/or glutamate-receptor blocking mechanisms of action. Thus, the present invention provides pharmaceutical compositions comprising as an active ingredient one of the non-psychotropic cannabinoids disclosed herein. These compositions are useful for the treatment or prevention of ischemia in the CNS as well as in other tissues such as kidney, lung, liver, heart and joints. The compositions will be neuroprotective and will be useful for the prevention or treatment of neurodegenerative disease as well as for glaucoma, pain, inflammation, and emesis.
The present invention discloses novel compounds that are effective in the alleviation and treatment of many of the abnormal states involving inflammation and toxicity. It will be noted that the compounds of the present invention may operate via diverse mechanisms to provide the neuroprotective and/or anti-inflammatory properties.
Certain embodiments of the present invention are particularly effective in alleviating and even preventing neurotoxicity due to excitatory amino acids, also referred to as glutamate neurotoxicity. Glutamate neurotoxicity may occur during acute injuries to the central nervous system (CNS), such as injuries due to prolonged seizures, compromised or reduced blood supply, deprivation of glucose supply and mechanical trauma. The present compositions are also effective in alleviating other damages to the CNS like damage resulting from poison-induced convulsions, including but not limited to those considered to be associated with amino acid receptors other than that of glutamate, for example glycine. Unexpectedly, neuroprotection is also a feature of some of the novel compounds that do not have a high affinity for the NMDA receptor.
The compositions of the present invention may also be effective in the treatment of certain chronic degenerative diseases that are characterized by gradual selective neuronal loss. In this connection, the compositions of the present invention are contemplated as therapeutically effective in the treatment of Alzheimer""s disease, Parkinson""s disease, Huntington""s disease and amyotrophic lateral sclerosis. Surprisingly, it has been shown experimentally that more preferred embodiments of this group of compounds can even promote nerve regeneration.
The present compositions are of special value in global hypoxic ischemic insults, in hypoxia, alone or in combination with blood flow reduction, such as cardiac, unstable myocardial, renal and hepatic ischemias, as well as in cases of cardiac arrest and in cases of abrupt occlusion of cerebral arteries (stroke).
The present compositions are also particularly useful as analgesics, a generally known attribute of this class of compounds. The present compositions are also of special value in inflammatory or immune diseases of 1) the nervous system, exemplified by multiple sclerosis and other autoimmune diseases, arthritis such as rheumatoid arthritis and other types of local or general inflammation, encephalitis and HIV-induced neurodegeneration; 2) the cardiovascular system, exemplified by myocardial infarction, coronary heart disease, restenosis of coronary vessels and myocarditis; and 3) the pulmonary system, exemplified by asthma or chronic obstructive pulmonary disease (COPD).
The invention also provides compositions that can inhibit the AA/PG signaling pathways that regulate or are regulated by COX-2, an example being the prevention or treatment of the occurrence or growth of gastrointestinal tumors such as colorectal cancer and colonic polyps.
The therapeutic agents of the present invention comprise novel derivatives of non-psychotropic cannabinoids.
A first embodiment of the present invention provides novel compounds according to formula (I): 
having the (3S,4S) configuration and being essentially free of the (3R,4R) enantiomer, wherein Axe2x80x94B indicates an optional 1(2) or 6(1) double bond,
R1 is
A) R3 where R3 is selected from the group consisting of
a) a linear or branched, saturated or unsaturated, carbon side chain comprising 1-8 carbon atoms interrupted by 1-3 heteroatoms; or
b) a saturated or unsaturated cyclic moiety or an aromatic or heterocyclic moiety having from 5-20 atoms comprising one or two-ringed structures, wherein each ring comprises 3-8 carbons interrupted by 1-4 heteroatoms, said heteroatoms in each independently selected from the group consisting of N, O, and S; wherein each ring optionally is further substituted with one or more groups selected from
i) C1-6 alkyl,
ii) C1-6 alkoxy,
iii) C1-6 alkylthio,
iv) Halo,
v) Carboxyl
vi) xe2x80x94CO2xe2x80x94C1-4 alkyl
vii) keto,
viii) nitro,
ix) a saturated or unsaturated cyclic moiety, or an aromatic or a heterocyclic moiety wherein each ring comprises 3-8 carbons interrupted by 0-4 heteroatoms, said heteroatoms in each independently selected from the group consisting of N, O, and S; wherein each ring optionally is further substituted with one or more groups selected from i)-viii) as defined above;
B) an amine or an amide substituted with at least one substituent as defined in R3 above;
C) a thiol, a sulfide, a sulfoxide, a sulfone, a thioester or a thioamide optionally substituted with one substituent as defined in R3 above; or
D) an ether xe2x80x94OR3 wherein R3 is as defined above;
G is (a) halogen, (b) C1-C5 alkyl, or (c) xe2x80x94OR wherein R is (axe2x80x2) xe2x80x94Rxe2x80x3, wherein Rxe2x80x3 is hydrogen or C1-C5 alkyl optionally containing a terminal xe2x80x94ORxe2x80x2xe2x80x3 or xe2x80x94OC(O)Rxe2x80x2xe2x80x3 moiety wherein Rxe2x80x2xe2x80x3 is hydrogen or C1-C5 alkyl, or (bxe2x80x2) xe2x80x94C(O)Rxe2x80x2xe2x80x3 wherein Rxe2x80x2xe2x80x3 is as previously defined, and
R2 is (a) C1-C12 alkyl, (b) xe2x80x94ORxe2x80x3xe2x80x3, in which Rxe2x80x3xe2x80x3 is a straight chain or branched C2-C9 alkyl which may be substituted at the terminal carbon atom by a phenyl group, or (c) xe2x80x94(CH2)nORxe2x80x2xe2x80x3 wherein n is an integer of 1 to 7 and Rxe2x80x2xe2x80x3 is hydrogen or C1-C5 alkyl.
For purposes of this specification C1-6 alkyl, C1-6 alkoxy and C1-6 alkylthio are intended to include saturated and unsaturated linear, branched and cyclic structures.
Currently more preferred compounds are those wherein G is hydroxy or lower acyloxy and wherein R2 is dimethylheptyl.
The present invention further relates to pharmaceutical compositions for the purposes set out above, comprising as an active ingredient a compound of the general formula (I): 
having the (3S,4S) configuration and being essentially free of the (3R,4R) enantiomer, wherein Axe2x80x94B indicates an optional 1(2) or 6(1) double bond,
R1 is
A) R3 where R3 is selected from the group consisting of
a) a linear or branched, saturated or unsaturated, carbon side chain comprising 1-8 carbon atoms interrupted by 1-3 heteroatoms; or
b) a saturated or unsaturated cyclic moiety or an aromatic or heterocyclic moiety having from 5-20 atoms comprising one or two-ringed structures, wherein each ring comprises 3-8 carbons interrupted by 1-4 heteroatoms, said heteroatoms in each independently selected from the group consisting of N, O, and S; wherein each ring optionally is further substituted with one or more groups selected from
i) C1-6 alkyl,
ii) C1-6 alkoxy,
iii) C1-6 alkylthio,
iv) Halo,
v) Carboxyl
vi) xe2x80x94CO2xe2x80x94C1-4 alkyl
vii) keto,
viii) nitro,
ix) a saturated or unsaturated cyclic moiety, or an aromatic or a heterocyclic moiety wherein each ring comprises 3-8 carbons interrupted by 0-4 heteroatoms, said heteroatoms in each independently selected from the group consisting of N, O, and S; wherein each ring optionally is further substituted with one or more groups selected from i)-viii) as defined above;
B) an amine or an amide substituted with at least one substituent as defined in R3 above;
C) a thiol, a sulfide, a sulfoxide, a sulfone, a thioester or a thioamide optionally substituted with one substituent as defined in R3 above; or
D) an ether xe2x80x94OR3 wherein R3 is as defined above;
G is (a) halogen, (b) C1-C5 alkyl, or (c) xe2x80x94OR wherein R is (axe2x80x2) xe2x80x94Rxe2x80x3, wherein Rxe2x80x3 is hydrogen or C1-C5 alkyl optionally containing a terminal xe2x80x94ORxe2x80x2xe2x80x3 or xe2x80x94OC(O)Rxe2x80x2xe2x80x3 moiety wherein Rxe2x80x2xe2x80x3 is hydrogen or C1-C5 alkyl, or (bxe2x80x2) xe2x80x94C(O)Rxe2x80x2xe2x80x3 wherein Rxe2x80x2xe2x80x3 is as previously defined, and
R2 is (a) C1-C12 alkyl, (b) xe2x80x94ORxe2x80x3xe2x80x3, in which Rxe2x80x3xe2x80x3 is a straight chain or branched C2-C9 alkyl which may be substituted at the terminal carbon atom by a phenyl group, or (c) xe2x80x94(CH2)nORxe2x80x2xe2x80x3 wherein n is an integer of 1 to 7 and Rxe2x80x2xe2x80x3 is hydrogen or C1-C5 alkyl.
For purposes of this specification C1-6 alkyl, C1-6 alkoxy and C1-6 alkylthio are intended to include saturated and unsaturated linear, branched and cyclic structures.
Currently more preferred compounds are those wherein G is hydroxy or lower acyloxy and wherein R2 is dimethylheptyl.
According to currently preferred embodiments of the present invention R1 is a heterocyclic moiety selected from the group consisting of an imidazolyl, an imidazolinyl, a morpholino, a piperidyl, a piperazinyl, a pyrazolyl, a pyrrolyl, a pyrrolidinyl, a triazolyl, and a tetrazolyl.
According to further currently preferred embodiments of the present invention R1 is a heterocyclic moiety selected from the group consisting of an imidazolyl, an imidazolinyl, a morpholino, a piperidyl, a piperazinyl, a pyrazolyl, a pyrrolyl, a pyrrolidinyl, a triazolyl, and a tetrazolyl, optionally further substituted wherein the substituent is selected from the group consisting of C1-6 alkyl, C1-6 alkyloxy, C1-6 alkylthio, keto, carboxy, nitro, saturated or unsaturated cyclic moieties or aromatic or heterocyclic moieties wherein each ring comprises 3-8 carbons interrupted by 1-4 heteroatoms, said heteroatoms in each independently selected from the group consisting of N, O, and S, wherein each ring optionally is further substituted with one or more groups selected from the group consisting of C1-6 alkyl, C1-6 alkyloxy, C1-6 alkylthio, keto, carboxy, or nitro.
According to more preferred embodiments of the present invention R1 is selected from the group consisting of imidazole, pyrazole, oxazole, isoxazole, tetrahydropyridine, pyrazoline, oxazoline, pyrrolidine, imidazoline, 2-thio-imidazole, 2-methylthio-imidazoline, 4-methyl-2-imidazoline, 4,4-dimethyl-2-imidazoline, methyl sulfide, methylsulfoxide, acetamido, benzamide, cyano, 1,2,4-triazole, 1,3,4-triazole, 1,2,3,4-tetrazole, 1,2,3,5-tetrazole, thiophene, phenyl, morpholine, thiomorpholine, thiazolidine, glycerol, piperazine, and tetrahydropyran.
According to additional more preferred embodiments of the present invention R1 is selected from the group consisting of mono or di-substituted amines wherein the substituent is selected from the group consisting of an C1-6 alkyl, C1-6 alkyloxy, C1-6 alkylthio, imidazolyl, an imidazolinyl, a morpholino, a piperidyl, a piperazinyl, a pyrazolyl, a pyrrolyl, a pyrrolidinyl, a triazolyl, and a tetrazolyl, optionally further substituted wherein the substituent is selected from the group consisting of C1-6 alkyl, C1-6 alkyloxy, C1-6 alkylthio, keto , carboxy, or nitro, wherein C1-6 alkyl, C1-6 alkoxy and C1-6 alkylthio are intended to include saturated and unsaturated linear, branched and cyclic structures.
It has been discovered that certain novel compounds of formula (I) are dexanabinol derivatives wherein R1 is a heterocyclic moiety. These compounds are preferred active agents of the presently claimed compositions for exhibiting efficient anti-inflammatory properties, including inhibition of prostaglandin synthesis, as well as inhibition of tumor necrosis factor production, and inhibition of nitric oxide production, in addition to providing NMDA receptor blocking and anti-oxidative activity.
It has also been discovered, unexpectedly, that certain novel compounds of formula (I) are dexanabinol derivatives wherein R1 is a substituted amine as defined above. These compounds are preferred active agents of the presently claimed compositions for exhibiting efficient anti-inflammatory properties, including inhibition of prostaglandin synthesis, as well as inhibition of tumor necrosis factor production, and inhibition of nitric oxide production, while being inactive or relatively inactive as NMDA receptor blockers.